Relaxin is a pregnancy hormone discovered in 1926 (Hisaw (1926) Proc. Soc. Exp. Biol. Med. 23: 661-663), based on its ability to relax the public ligament in guinea pig. Mature human relaxin is a hormonal peptide of approximately 6000 daltons known to be responsible for remodelling the reproductive tract before parturition, thus facilitating the birth process. A concise review of relaxin was provided by Sherwood, D. in The Physiology of Reproduction, Chapter 16, “Relaxin”, Knobil, E. and Neill, J., et al. (eds.), (Raven Press Ltd., New York), pp. 585-673 (1988). Relaxin has local autocrine and/or paracrine roles that contribute to connective tissue remodeling at the maternal-fetal interface during late pregnancy and at parturition, including an increase in the expression of the genes, proteins, and enzyme activities of the matrix metalloproteinases interstitial collagenase (MMP-1), stromelysin (MMP-3), and gelatinase B (MMP-9).
In humans, the relaxin gene family contains a total of seven members: relaxin H1 (RLN1), relaxin H2 (RLN2), relaxin 3/INSL7 (RLN3), INSL3/RLF, INSL4/EPIL, INSL5/RIF2, and INSL6/RIF1 (Hudson et al. (1983) Nature 301:628-631; Hudson et al. (1984) EMBO Journal 3:2333-2339; U.S. Pat. Nos. 4,758,516 and 4,871,670). The primary translation product of H2 relaxin is a preprorelaxin consisting of a 24 amino acid signal sequence followed by a B chain of about 29 amino acids, a connecting peptide of 104-107 amino acids, and an A chain of about 24 amino acids. Among these family members, RLN2 and INSL3 signal through two leucine-rich repeat-containing GPCRs, LGR7 (RFXR1) and/or LGR8 (RFXR2). Whereas RLN2 is capable of activating both LGR7 and LGR8, INSL3 is a selective ligand for LGR8. In addition to the better characterized RLN2 and INSL3, RLN3 was shown to activate LGR7, GPCR135, and GPCR142, but not LGR8 (6-10); therefore, the relaxin family peptides exhibit overlapping specificity on the activation of LGR7 and LGR8.
Evidence has accumulated to suggest that relaxin is more than a hormone of pregnancy and acts on cells and tissues other than those of the female reproductive system. Relaxin causes a widening of blood vessels (vasodilatation) in the kidney, mesocaecum, lung and peripheral vasculature, which leads to increased blood flow or perfusion rates in these tissues (Bani et al (1997) Gen. Pharmacol. 28, 13-22). It also stimulates an increase in heart rate and coronary blood flow, and increases both glomerular filtration rate and renal plasma flow (Bani et al (1997) Gen. Pharmacol. 28, 13-22). The brain is another target tissue for relaxin where the peptide has been shown to bind to receptors. In addition to the role in remodeling of reproductive tissues, relaxin has been shown to effect endometrial differentiation during embryo implantation, nipple and mammary gland development, angiogenesis, wound healing, and renal cardiovascular responses. Furthermore, recent studies have shown that relaxin prolongs the survival of tumor-bearing mice by enhancing the degradation of the extracellular matrix, thereby slowing down tumor growth.
In contrast, INSL3 is essential for testis descent in rodents and contributes to the regulation of, 1) male germ cell apoptosis; 2) initiation of meiotic progression of arrested oocytes in preovulatory follicles; and 3) the positioning of the female gonad during development. Although the importance of LGR7 and LGR8 in human RLN1 and RLN2 signaling remains to be studied, in vitro evidence indicated that human RLN2 could effect LGR8 signaling in vivo. Based on its pleiotropic effects on tissue remodeling, relaxin has been the subject for clinical trials aimed to treat scleroderma, pre-eclampsia, congestive heart failure, and to enhance cervical ripening during the third trimester of pregnancy. The finding that human RLN2 is capable of activating both LGR7 and LGR8 raises the possibility that clinical applications of human RLN2 could pose unwanted responses in the LGR8 signaling pathway in patients, which could include effects on spermatogenesis and ovarian follicle development.
Therefore, a better understanding of the molecular mechanisms underlying the interaction of human RLN2 and its receptors, as well as the generation of an LGR7-specific human relaxin analog are of great interest.